It is known that a protease, which is a proteolytic enzyme, is responsible for the onset and progression of various diseases such as hypertension, thrombosis, pancreatitis, cancer, an Alzheimer disease, pulmonary emphysema, a nerve degeneration disease, an allergic disease, muscular dystrophy, a rheumatic disease, osteoporosis and a periodontal disease (Protein, Nucleic Acid, and Enzyme, vol. 42, No. 14 (1997); and Experimental Medicine, vol. 17, No. 15 (1999)), and inhibitor substances of protease, namely, protease inhibitors are expected as a target of medicines.
An α-ketoamide compound, which has been reported (Japanese Provisional Patent Publication No. 149166/1992; Japanese Provisional Patent Publication No. 211648/1992; Japanese PCT Provisional Patent Publication No. 504547/1994; WO9816512; J. Med. Chem., 39, 4089 (1996); and Exp. Opin. Ther. Patents., 8, 1707 (1998)) to have an inhibiting activity with respect to protease, especially serine protease (elastase, tryptase, trypsin, chymotrypsin, and prolyl endopeptidase) and cysteine protease (calpain, cathepsin B, and cathepsin L), is a compound expected to possibly have an inhibiting activity with respect to cathepsin K, which has recently been reported to be closely responsible for bone metabolism.
As a representative synthesis method for a protease inhibitor having an α-keto amide structure, (A) J. Med. Chem., 36, 3472 (1993) is known, and further, as a representative synthesis method for optically active substances thereof, (B) J. Med. Chem., 37, 2918 (1994) is known.
By the above (A) method, an α-keto amide compound which is a desired compound cannot be obtained in the form of an optically active substance. Further, the above (B) method has the following problems: (1) an optically active amino acid as a starting material is expensive; (2) since an amino acid is used as a starting material, only a limited substituent can be introduced into the oxirane ring as substituent R1 (see general formula (I)); and (3) an α-hydroxy group in the reaction precursor cannot be stereoselectively controlled, and therefore a product is obtained in the form of a diastereomer mixture and satisfactory purification for the product is difficult. Thus, the above methods are not satisfactory as an industrial production process.
The present inventors have conducted extensive and intensive studies with a view toward solving the problems accompanying the prior art. As a result, they have found raw materials (an epoxycarboxamide compound, an azide compound, and an amino alcohol compound) for preparation of an α-keto amide compound, which are advantageous not only in that substituent R1 is not restricted by the amino acid structure, but also in that an α-keto amide compound can be stereoselectively formed, and thus have completed the present invention.